An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date.
In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done.
From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36–66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3–6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6–10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats.
Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.
We report here a familial cluster of unexplained pneumonia due to 2019-nCoV. Six of seven family members had radiological changes of viral pneumonia, among whom five (patients 1, 2, 4, 5, and 7) tested positive for 2019-nCoV by RT-PCR. Five patients (patients 1, 2, 3, 4, and 7) had associated symptoms at the time of presentation. Complete genome sequences of the two strains from patients 2 and 5 showed almost complete nucleotide identity with each other, and were closest to the bat SARS-related coronaviruses reported in 2018. Several possible scenarios of transmission exist. The first and most likely scenario is that one virologically documented patient with pneumonia (patient 1) acquired the infection from a Wuhan hospital while visiting their relative (relative 1) and then patients 1–5 transmitted the virus to patient 7 on returning to Shenzhen. The second scenario is that patients 1–5 have directly acquired the infection from relatives 2–5 and transmitted it to patient 7 on returning to Shenzhen. But this scenario is less likely because patients 1–5 developed symptoms before relatives 2–5. The third scenario is that patients 1–5 acquired the infection from an unknown common source in Wuhan and transmitted it to patient 7 when back in Shenzhen. For the patients' relatives (relatives 2–5), they could have acquired the infection from the hospital or the community, although no virological confirmation was possible and they had no animal contacts, game food, or visits to the Huanan seafood wholesale market. Notably, patient 1 or patient 3 who had visited Wuhan hospital might have been infectious before symptom onset because patient 5 was shedding virus without symptoms. These findings suggested that person-to-person transmission and intercity spread of 2019-nCoV by air travel are possible, supporting reports of infected Chinese travellers from Wuhan being detected in other geographical regions. Many of the epidemiological, clinical, laboratory, and radiological features of this novel coronavirus pneumonia were similar to those of SARS patients in 2003.The incubation period of the Wuhan pneumonia appeared similar to that of SARS. The attack rate is rather high, up to 83% if we included the five patients (patients 1, 2, 3, 4, and 5) with unexplained ground-glass radiological changes of the lungs on CT scan as the case definition in this family outbreak after visiting Wuhan. A rather unexpected finding from the lung CT scan of patient 5, which was done on the insistence by the nervous parents, also showed ground-glass pneumonic changes. Patient 5 was later confirmed virologically to have an asymptomatic infection. Although asymptomatic patients with SARS were uncommon, they were documented in our retrospective study in the minor 2004 SARS outbreak after reopening of the wildlife market in Guangzhou. Notably, patients 3 and 4 were afebrile at presentation to our hospital. These cryptic cases of walking pneumonia might serve as a possible source to propagate the outbreak. Further studies on the epidemiological significance of these asymptomatic cases are warranted.
The symptoms of this novel pneumonia were also non-specific. The three oldest patients in this family with comorbidities had more severe systemic symptoms of generalised weakness and dry cough. As expected, they might have decreased total white blood cell, lymphocyte, or platelet counts, with also extended activated thromboplastin time and increased C-reactive protein level. The multifocal ground-glass changes on lung CT scan were typical of viral pneumonia. Their lung involvement was also more diffuse and extensive than those of the younger patients, whose blood test results were largely normal. Patient 4, who had a history of chronic sinusitis, might have a bacterial superinfection because he had a productive cough instead of a dry cough. He also had a high white blood cell count, although the bacterial test was negative.
Interestingly, the two younger adults (patients 3 and 4) initially had diarrhoea, which was also reported in 10·6% (15 of 142) of our SARS patients at presentation;however, the subsequent faecal samples of patients 3 and 4 that were collected 9–10 days after symptom onset were negative for the virus after the diarrhoea had long subsided. Up to 30% of patients with Middle East respiratory syndrome coronavirus (MERS-CoV) also have diarrhoea.Subgenomic RNA indicating viral replication was seen in faecal samples of patients with MERS.Moreover, MERS-CoV was shown to survive in simulated fed gastrointestinal juice and the ability to infect intestinal organoid models.Diarrhoea and gastrointestinal involvement are well known in coronavirus infections of animals and humans.On microbiological testing, we did not find any evidence of other known respiratory viral or bacterial infections, but specific RT-PCR assays for two widely separated genome targets—the highly conserved RdRp and the highly variable S genes—were positive for this novel 2019-nCoV. Two complete genome sequences of this novel coronavirus were recovered from the nasopharyngeal swab of patient 2 and the sputum sample of patient 5 with an earlier cycle threshold value indicating a higher viral load. Patient 2 had more underlying comorbidities and clinical features and radiological findings of more severe disease than the other patients included here. Moreover, the serum sample of patient 2 was also positive for 2019-nCoV, which might indicate some virus spillover from the more severely infected lung into the systemic circulation, as previously reported in patients with SARS.22 Sputum samples were available for testing from patients 5 and 7. The cycle threshold values of the sputum samples were 8–13 cycles earlier than those of throat swabs, indicating higher viral loads detected in the lower respiratory tract. This finding is consistent with the observations in patients with MERS who had higher viral loads in lower respiratory tract samples than in upper respiratory tract samples.23 Thus, repeat testing of upper respiratory tract samples or testing of lower respiratory tract samples are warranted in clinically suspected cases with an initially negative result in nasopharyngeal or throat swab. Unlike our patients in the 2003 SARS outbreak,we found no evidence of viral shedding in urine and faeces in these six patients. However, improved systematic serial collection and testing of an increased number of such samples is warranted.Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses, capable of rapid mutation and recombination. They are classified into alphacoronaviruses and betacoronaviruses, which both have their gene source from bats and are mainly found in mammals such as bats, rodents, civets, and humans; and gammacoronaviruses and deltacoronaviruses, which both have their gene source from birds and are mainly found in birds.Phylogenetic analysis of the PCR amplicon fragments from five of our six patients and the complete virus genome of 29·8 kilobases from patients 2 and 5 showed that the virus is a novel betacoronavirus belonging to the lineage B or subgenus sarbecovirus, which also includes the human SARS coronavirus. The genome of our virus strains are phylogenetically closest to the bat SARS-related coronaviruses first found in the Chinese horseshoe bats, Rhinolophus sinicus, captured in Zhoushan, Zhejiang province, China, between 2015 and 2017.Notably, the first SARS-related coronavirus was also discovered in the R sinicus found in Hong Kong, and central and south China in 2005.The full virus genome had about an 89% nucleotide identity with bat-SL-CoVZC45, which makes it a new species. Moreover, the Spike protein of our virus has an 84% nucleotide identity with the bat-SL-CoVZC45 coronavirus and an 78% nucleotide identity with the human SARS coronavirus. Although substantial genetic differences exist between this and other betacoronaviruses, cross reactions in RT-PCR or antibody assays for SARS or other betacoronaviruses are possible if the primers and antigenic epitopes are not carefully chosen, as previously reported.Further studies on the optimal diagnostic tests are warranted.
In summary, an outbreak of novel coronavirus is ongoing at Wuhan in the winter of 2019–20. Similar to the 2003 SARS outbreak in Guangzhou, Wuhan is also a rapidly flourishing capital city of the Hubei province and the traffic hub of central China. Moreover, both outbreaks were initially connected to wet markets where game animals and meat were sold. In the case of SARS, person-to-person transmission was efficient and super-spreading events had led to major outbreaks in hotels and hospitals. Learning from the SARS outbreak, which started as animal-to-human transmission during the first phase of the epidemic, all game meat trades should be optimally regulated to terminate this portal of transmission. But as shown in this study, it is still crucial to isolate patients and trace and quarantine contacts as early as possible because asymptomatic infection appears possible (as shown in one of our patients), educate the public on both food and personal hygiene, and alert health-care workers on compliance to infection control to prevent super-spreading events. Unlike the 2003 SARS outbreak, the improved surveillance network and laboratory capability of China was able to recognise this outbreak within a few weeks and announced the virus genome sequences that would allow the development of rapid diagnostic tests and efficient epidemiological control. Our study showed that person-to-person transmission in family homes or hospital, and intercity spread of this novel coronavirus are possible, and therefore vigilant control measures are warranted at this early stage of the epidemic.
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